Genetics of common complex psychiatric disorders II

Mark James Adams

Part 2: Molecular genetics

Mark James Adams
Division of Psychiatry
mark.adams@ed.ac.uk
Genetics and Environmental Influences on Behaviour and Mental Health

Structure of DNA

Gene structure

Types and sizes of genetic variants

Chromosomes

Diploid (two copies of each chromosome)

Single Nucleotide Polymorphisms (SNP)

  • Single base of DNA is substituted with another.
  • Occur in 1 of every 100 - 1000 basepairs (bp).
  • Currently, ± 1.2B SNPs are known.
  • Labelled with a dbSNP Reference ID (“rs number”)

Canidate gene studies (circa 2000)

Example: Catechol-O-methyltransferase (COMT)

SNP rs4680 G>A substitution (missense variant) results in amino acid change from valine to methionine at codon 158 (Val158Met).

Genome-wide associations studies (GWAS) (2007 - today)

  • Candidate gene findings did not replicate
  • Power analysis: candidate gene study sample sizes were vastly too small
  • Alternative: Assay the whole genome (hundreds of thousands or millions of variants)
  • Hypothesis-free testing

Conducting a GWAS

  • Two alleles: A and a
  • Three genotypes: AA, Aa, aa
  • Arbitrarily select one allele (A) as the effect allele
  • For each subject, count number of effect alleles: \(x = 0, 1, 2\)

  • Regress on phenotype \(Y\)
  • Linear regression: \(Y \sim \alpha + \beta x + \mathrm{covariates}\)
  • Logistic regression: \(\mathrm{Prob}(Y= 1) \sim \mathrm{logit}^{-1}(\alpha + \beta x + \mathrm{covariates})\)
  • Repeat for all markers

15+ years of GWAS

GWAS data

CHROM POS ID REF ALT P OR AF
chr1 1006415 rs145588482 TGGCAGCTC T 0.0004688 0.583384 0.01293
chr1 1007256 rs76233940 G A 0.0004016 0.579783 0.01301
chr1 1341559 rs376494450 C T 0.0001512 1.320130 0.02706
chr1 1480224 rs71628972 A G 0.0007602 1.412750 0.01319
chr1 2035619 rs111334586 C T 0.0009206 1.413370 0.01209
chr1 2213349 rs262695 A G 0.0008815 0.904873 0.32073

Plotting GWAS results

Plotting GWAS results